Nonsyndromic recessive deafness DFNB18 and Usher syndrome type IC are allelic mutations of USHIC

Abstract

Human chromosome 11 harbors two Usher type I loci, USHIB and USHIC, which encode myosin VIIA and harmonin, respectively. The USHIC locus overlaps the reported critical interval for nonsyndromic deafness locus DFNB18. We found an IVS12+5G-->C mutation in the USHIC gene, which is associated with nonsyndromic recessive deafness ( DFNB18) segregating in the original family, S-11/12. No other disease-associated mutation was found in the other 27 exons or in the intron-exon boundaries, and the IVS12+5G-->C mutation was not present in 200 representative unaffected individuals ascertained from the same area of India. An exon-trapping assay with a construct harboring IVS12+5G-->C generated wildtype spliced mRNA having exons 11 and 12 and mRNA that skipped exon 12. We conclude that mutations of USHIC can cause both Usher syndrome type IC and nonsyndromic recessive deafness DFNB18.

Usher I syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells

“…With the exception of the tip link (see below), the roles of the links in the growing and mature hair bundles are unknown. However their conservation throughout evolution, from fish (Sollner et al, 2004;Seiler et al, 2005), mice (Alagramam et al, 2001a;Di Palma et al, 2001;Wilson et al, 2001) to humans (Bork et al, 2001;Ahmed et al, 2002), strongly argues for their functional relevance. Their molecular composition is a key element because they will behave as more or less elastic connectors when submitted to the force of the mechanical stimulation, depending on their extracellular domain composition, their possible oligomerisation and binding to other ligands.…”

“…Mutations in four of the USH1 genes have also been reported to cause isolated recessive (DFNB) or dominant (DFNA) forms of deafness: DFNB2 and DFNA11 (USH1B) (Liu et al, 1997a;Liu et al, 1997b;Weil et al, 1997), DFNB18 (USH1C) (Ahmed et al, 2002;Ouyang et al, 2002), DFNB12 (USH1D) (Bork et al, 2001) and DFNB23 (USH1F) (Ahmed et al, 2002). The mutations causing these isolated forms of deafness are usually expected to be less deleterious for the protein activities than those observed in USH1 patients.…”

Profound, prelingual nonsyndromic deafness maps to chromosome 10q21 and is caused by a novel missense mutation in the Usher syndrome type IF gene PCDH15

“…Of the seven USH1 loci that have been mapped (USH1B-USH1H), missense mutations in three of these proteins, namely Myosin 7A (MYO7A: USH1B, DFNA11/ DFNB2), 37 -41 Harmonin (USH1C, DFNB18) 42 and cadherin-23 (CDH23, USH1D, DFNB12) 43 also cause nonsyndromic hearing loss. This study also supports a role for PCDH15 in isolated deafness.…”

Usher syndrome type 1 due to missense mutations on bothCDH23 alleles: investigation of mRNA splicing

“…It has been estimated that approximately 1.6% of disease-causing missense mutations in human genes probably affect mRNA splicing [Krawczak et al, 2006]. For three genes underlying Usher syndrome type 1, there is a clearcut genotype-phenotype correlation, with truncating mutations causing the syndromic phenotype, while missense/in-frame alterations lead to non-syndromic deafness (USH1C and USH1C/DFNB18, CDH23 and USH1D/DFNB12, PCDH15 and USH1F/DFNB23; [Ahmed et al, 2003;Ahmed et al, 2002;Bitner-Glindzicz et al, 2000;Bolz et al, 2001;Bork et al, 2001;Ouyang et al, 2002]). The four CDH23 missense mutations investigated herein have been described in homozygous state in patients with USH1.…”